Lack of LDL receptor aggravates learning deficits and amyloid deposits in Alzheimer transgenic mice
Abstract
Emerging evidence indicates that cholesterol metabolism affects the pathogenesis of Alzheimer's disease (AD). The LDL receptor (LDLR) is obligatory in maintaining cholesterol homeostasis in the periphery. To investigate the role of LDLR in the development of AD-like behavior and pathology, Tg2576 mice, a well-characterized transgenic mouse model of AD, with different genotypes of LDLR were generated. Here we show that LDLR-deficient Tg2576 mice developed hypercholesterolemia and age-dependent cerebral beta-amyloidosis. Before the manifestation of amyloid-beta (Abeta) deposition, these mice displayed hyperactivity, reduced anxiety, and impaired spatial learning regardless of LDLR genotypes. After the manifestation of Abeta deposition, LDLR-deficient Tg2576 mice showed more spatial learning deficits than LDLR-intact Tg2576 mice. Although LDLR genotypes did not affect the expression level of the amyloid-beta precursor protein transgene, there was a significant increase in Abeta deposition accompanied with an increase of apoE expression in LDLR-deficient Tg2576 mice. Our results suggest that the LDLR plays a role in the development of Alzheimer-type learning impairment and amyloidosis and can be a novel therapeutic target for AD.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Lack of LDLR is associated with increased amyloid deposition in Tg2576 mice.
“In contrast, lack of LDLR was associated with increased amyloid deposition in Tg2576 mice (Cao et al., 2006).”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as Cao et al., 2006
Inactivation of Ldlr or Lrp1 increases, whereas overexpression of LDLR decreases, ApoE protein in the brain.
“Inactivation of the Ldlr or Lrp1 gene increases, whereas overexpression of LDLR decreases, ApoE protein in the brain (19, 35–37).”
From The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and Aβ amyloidosis (2015) · cites this paper as [35]
Deletion of Ldlr increases APOE levels in the brain.
“Indeed, deletion of Ldlr increased APOE levels in the brain. 59 , 60 , 61”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [60]
Deletion of either LDLR or LRP1 significantly increases apoE levels in brain.
“deletion of either LDLR or LRP1 significantly increases apoE levels in brain”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Cao et al 2006
LDLR deficiency was associated with increased amyloid deposition in Tg2576 APP transgenic mice.
“In addition, LDLR deficiency was associated with increased amyloid deposition in Tg2576 APP transgenic mice (Cao et al., 2006).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Cao et al., 2006
Cites
A Receptor-Mediated Pathway for Cholesterol Homeostasis
Brown, M. S., & Goldstein, J. L. (1986) · Science · doi:10.1126/science.3513311 · Cited by 5,703 · see citing works
Lack of apolipoprotein E dramatically reduces amyloid β-peptide deposition
Bales, K. R., Verina, T., Dodel, R. C., Du, Y., Altstiel, L., Bender, M., Hyslop, P., Johnstone, E. M., Little, S. P., Cummins, D. J., et al. (1997) · Nature Genetics · doi:10.1038/ng1197-263 · Cited by 830 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661 · see citing works
Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C.-C., & Bu, G. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0228-7 · Cited by 1,425 · see citing works
Yeh, F. L., Wang, Y., Tom, I., Gonzalez, L. C., & Sheng, M. (2016) · Neuron · doi:10.1016/j.neuron.2016.06.015 · Cited by 943 · see citing works
Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease
Holtzman, D. M., Herz, J., & Bu, G. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006312 · Cited by 782 · see citing works
ApoE and Aβ in Alzheimer’s Disease: Accidental Encounters or Partners?
Kanekiyo, T., Xu, H., & Bu, G. (2014) · Neuron · doi:10.1016/j.neuron.2014.01.045 · Cited by 608 · see citing works
Cao, D., Lu, H., Lewis, T. L., & Li, L. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m703561200 · Cited by 336 · see citing works
Self-citationKim, J., Castellano, J. M., Jiang, H., Basak, J. M., Parsadanian, M., Pham, V., Mason, S. M., Paul, S. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.11.013 · Cited by 274 · see citing works
Kim, J., Jiang, H., Park, S., Eltorai, A. E. M., Stewart, F. R., Yoon, H., Basak, J. M., Finn, M. B., & Holtzman, D. M. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.3773-11.2011 · Cited by 199 · see citing works
Basak, J. M., Verghese, P. B., Yoon, H., Kim, J., & Holtzman, D. M. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.288746 · Cited by 192 · see citing works
Castellano, J. M., Deane, R., Gottesdiener, A. J., Verghese, P. B., Stewart, F. R., West, T., Paoletti, A. C., Kasper, T. R., DeMattos, R. B., Zlokovic, B. V., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1206446109 · Cited by 154 · see citing works
Wilhelmus, M. M. M., Otte-Höller, I., van Triel, J. J. J., Veerhuis, R., Maat-Schieman, M. L. C., Bu, G., de Waal, R. M. W., & Verbeek, M. M. (2007) · The American Journal of Pathology · doi:10.2353/ajpath.2007.070050 · Cited by 138 · see citing works
Functional Roles of the Interaction of APP and Lipoprotein Receptors
Pohlkamp, T., Wasser, C. R., & Herz, J. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00054 · Cited by 92 · see citing works
Lipid metabolism in Alzheimer’s disease
Liu, Q., & Zhang, J. (2014) · Neuroscience Bulletin · doi:10.1007/s12264-013-1410-3 · Cited by 101 · see citing works
Katsouri, L., & Georgopoulos, S. (2011) · PLoS ONE · doi:10.1371/journal.pone.0021880 · Cited by 72 · see citing works
ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease
Li, Y., Macyczko, J. R., Liu, C.-C., & Bu, G. (2022) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2022.03.011 · Cited by 61 · see citing works
Choi, J., Gao, J., Kim, J., Hong, C., Kim, J., & Tontonoz, P. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aad1904 · Cited by 49 · see citing works
Wang, S.-H., Huang, Y., Yuan, Y., Xia, W.-Q., Wang, P., & Huang, R. (2014) · Lipids in Health and Disease · doi:10.1186/1476-511x-13-175 · Cited by 44 · see citing works
Matsumoto, K., Chiba, Y., Fujihara, R., Kubo, H., Sakamoto, H., & Ueno, M. (2015) · Histochemistry and Cell Biology · doi:10.1007/s00418-015-1366-7 · Cited by 46 · see citing works
Li, L., Cao, D., Desmond, R., Rahman, A., Lah, J. J., Levey, A. I., & Zamrini, E. (2008) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000164271 · Cited by 45 · see citing works
Self-citationTherapeutic Idol reduction ameliorates amyloidosis and improves cognitive function in APP/PS1 mice
Gao, J., Littman, R., Diamante, G., Xiao, X., Ahn, I. S., Yang, X., Cole, T. A., & Tontonoz, P. (2020) · Molecular and Cellular Biology · doi:10.1128/mcb.00518-19 · Cited by 15 · see citing works
Karahan, H., Hartigan, K., Al‐Amin, M. M., John, S. K., McCord, B., Wijeratne, H. R. S., Acri, D. J., Smith, D. C., Dabin, L. C., Cordero, H. M. R., et al. (2025) · Alzheimer's & Dementia · doi:10.1002/alz.70949 · Cited by 2 · see citing works
- Authors
- Cao, D., Fukuchi, K.-I., Wan, H., Kim, H., & Li, L.
- Affiliations
- University of Alabama at Birmingham (US)
- Corresponding author
- Li, Ling
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2006-11
- Volume
- 27
- Issue
- 11
- Pages
- 1632-1643
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2098796119
- Cited by
- 106
- References
- 2
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 3 · 2023: 1 · 2022: 2 · 2020: 7 · 2019: 3 · 2017: 2 · 2016: 3 · 2015: 8 · 2014: 13 · 2013: 5 · 2012: 9
- FWCI
- 3.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- University of Minnesota
- National Institute on Aging (R21AG025949, AG025949)
- National Institute of Neurological Disorders and Stroke (NS 43947, R01NS043947)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- LDL receptor, Alzheimer's disease, Tg2576 mice, amyloid-beta deposition, hypercholesterolemia, spatial learning deficits, cholesterol metabolism, apolipoprotein E, amyloid precursor protein, anxiety, hyperactivity, therapeutic target
- MeSH terms
- Alzheimer Disease, Amyloidosis, Animals, Cholesterol, Disease Models, Animal, Female, Hypercholesterolemia, Male, Memory, Mice, Transgenic, Receptors, LDL, Amyloid beta-Peptides, Maze Learning, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
